The effect of different dosage of intranasal dexmedetomidine on preventing emergence delirium or agitation in children: A network meta-analysis of randomized controlled trials

Background The clinical evidence for the effects of different doses of intranasal dexmedetomidine on emergence delirium/ emergence agitation (ED/EA) in children is lacking. Methods We searched the PubMed, EMBASE and Cochrane Library from the establishment of the databases until December 30, 2023. All randomized controlled trials that evaluated the effect of different dosage of intranasl dexamedetomidine in children younger than 18 years on postoperative ED/ EA were included. Data analysis was conducted using R 4.3.0. Results A total of 15 randomized controlled trials involving 1566 children were included. Compared to 0.5 μg/kg (RR = 4.81, 95%CI = 1.66–13.94), and normal saline (RR = 8.23, 95%CI = 4.63–14.65), intranasal dexmedetomidine at doses of 2 μg/kg significantly reduced the incidence of ED/ EA in children. 2 μg/kg was the most effective dosage in reducing the incidence of ED/ EA (Probability of rank = 0.75), the incidence of severe ED/ EA (Probability of rank = 0.45), and ED/ EA score (Probability of rank = 0.65). Moreover, intranasal dexmedetomidine at doses of 2 μg/kg significantly reduced the PACU pain compared to 0.5 μg/kg (RR = 0.42, 95%CI = -0.22–1.06), 1 μg/kg (RR = 0.18, 95%CI = -0.26–0.63), 1.5 μg/kg (RR = 1.00, 95%CI = -0.54–0.75), and normal saline (RR = 8.23, 95%CI = 4.63–14.65), with a probability of rank = 0.45. Conclusion 2μg/kg intranasal dexmedetomidine is the optimum dose for reducing the occurrence of ED/ EA and postoperative pain. However, further research is required to verify our findings.


Introduction
Emergence delirium or emergence agitation (ED/ EA) are common postoperative complications in children that characterized by behaviors such as crying, fear, restlessness, and disorientation occurring in the early stages during anesthesia recovery period according to diagnostic criteria of the Pediatric Anesthesia Emergence Delirium (PAED) scale [1].Metaanalysis by Farag et al. [2] showed the incidence of ED/ EA was 31.4% in pediatric patients underwent sevoflurane anesthesia and surgery.ED/EA in children led to serious consequences such as vomiting, aspiration, laryngospasm, and notably extended hospital stays [3,4].Therefore, effective interventions to reduce ED/ EA in pediatrc patients is an issues to be solved.
Dexmedetomidine (DEX), a highly selective α2-adrenoceptor agonist, was a promising medication in this context [5].Until now, intranasal DEX has been widely used in pediatric patients and showed effectively in reducing the incidence of ED/ EA [6,7].Li et al. [8] indicated that children under 3 years, DEX takes sedative and analgesic effect in 20 minutes, maintains a two hour time, and has less effect on systemic vascular and respiratory depression, moreover, intranasal DEX would not induce nasal irritation, making it a suitable option for preoperative medication.However, the dosage of intranasal DEX differed among studies, and the optimal dose for preventing postoperative ED/ EA remains inconclusive.
This network meta-analysis aimed to investigate the optimal dose for preventing postoperative ED/ EA in children, and provided clinical medication guidance.

Methods
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (S1 Table ).

Search strategy
We conducted a systematic search in PubMed, Embase, Cochrane Library, and Web of Science databases for studies from the databases esteblished up to December 12, 2023 without restrictions on language.Keywords used were ("Dexmedetomidine") and ("Child" or "Adolescent" or "Pediatrics" or "Youth" or "Teen") and (intranasal) and ("postoperative delirium" or "postoperative agitation" or "emergenc delirium" or "emergenc agitation").Search strategies were shown in S1 File.

Eligibility criteria
Inclusion criteria were: 1) Children younger than 18 years.2) American Society of Anesthesiologists (ASA) physical status I-III.3) DEX group received intranasal DEX as premedication before anesthesia, and control group received normal saline.4) The incidence of ED/ EA in DEX group and control group both could be converted into dichotomous variable.5) Randomized controlled trial (RCT).Exclusion criteria were: 1) Other intervention that influenced ED/ EA was used.2) Letter, abstract.

Data extraction and bias assessment
Two researchers strictly screened the title and abstracts and full texts according to the eligibility criteria, then extracted characteristics of each study, such as authors, publication year, country, age, gender, and sample size.The primary outcome was the incidence of ED/ EA, which was assessed according to Pediatric Anesthesia Emergence Delirium score (PAED), or other delirium and agitation scale.ED/ EA was defined as PEAD score>10 or the equal level as the other grading scale.Secondary outcome included severe ED/ EA which was defined as PEAD score>14 or the equal level as the other grading scale, ED/ EA score, PACU pain score which was assessed according to 1-10 grading scale, parent's satisfaction which was assesed according to 1-10 grading score, length of PACU stay, postoperative nausea and vomiting, breath holding.Cross-checked were conducted and a third researcher joined the discussion for consensus in cases of disagreement.
The quality assessment of included studies was independently conducted by two researchers using the Cochrane Risk of Bias tool Version 2.0 (RoB2), including five aspects: bias arising from the randomization domains, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, bias in selection of the reported result.Any discrepancies were resolved through consultation with a third reviewer.To assess publication bias, funnel plots was performed and checked its symmetry if articles were more than nine.

Data synthesis and analysis
All the data analyses were performed by R 4.3.0.Odd ratio (OR) with 95% CI was calculated for dichotomous variable, and standard mean difference (SMD) with 95% CI was calculated for continuous variable.Heterogeneity was determined using I 2 , a random-effects model was employed regardless of heterogeneity.
Network diagram was performed to show the direct and indirect comparison between different dosages, the size of the nodes represents the sample size of each dosage, and the thickness of the lines connecting the nodes indicated the number of studies directly compared between two dosage.When testing global consistency, P>0.05 indicates that there was no overall inconsistency, and the consistency model was used, otherwise non-consistency model was used.League tables were performed to summarize the different dosages of outcomes containing both direct and indirect comparisons.We calculated the probabilities of ranking in all different dosages to rank the effect of different dosages on outcomes.
The PRISMA flowchart was shown in Fig 1 , The characteristics of included studies was shown in Table 1.

Quality risk of bias and publication bias
There were no risk of bias in randomization and deviations from intended interventions in all 15 RCTs.The overall risk was "some concerns" mainly came from not reporting if all patient data was available, as shown in S1 Fig.
Funnel plots of publication bias in the 15 RCTs in all outcomes revealed general symmetry, indicated no signifcant publication bias, as shown in S2 Fig.

Network meta-analysis
Primary outcome.The incidence of ED/ EA. 13 studies reported the incidence of ED/ EA, 2 μg/kg was the most reported dosage, as shown in network plot in Fig 2A .The consistency model showed no significant inconsistency showed between the direct comparisons and     There were four studies each reporting parent's satisfaction, length of PACU stay, postoperative nausea and vomiting, breath holding.Since limited data, we did not pool these outcomes, as shown in S2 File.

Discussion
Our network meta-analysis found that 2μg/kg preoperative intranasal dexmedetomidine was the most effective doses in reducing the incidence of postoperative ED/ severity of EA, ED/ EA, and ED/ EA score compared with 0.5μg/kg, 1μg/kg, 1.5μg/kg, and normal saline in children.In addition, 2μg/kg was also the most effective in relieving pain in PACU.These findings were helpful for the guidance of clinical medication.
A lot of research supported dexmedetomidine can prevent postoperative delirium.Jen et al. [22] reported that oral dexmedetomidine was effective in reducing sudden agitation in pediatric patients.Dexmedetomidine might prevent ED/ EA in children by promoting NLRP3 inflammasome degradation [23] and reducing hippocampal brain inflammation [24] through the autophagy-ubiquitin pathway, thereby protecting nerves and improving cognitive dysfunction.
At present, only one meta-analysis by Na et al. [25] reported the relationship between intranasal dexmedetomidine and ED/ EA, and concluded that intranasal dexmedetomidine reduced ED/ EA after general anesthesia from 33.2% to 13.6%.This was similar to our findings.However, their study included few studies, mixed drug types in control group, including midazolam, clonidine, ketamine, etc., and no subgroup analysis of different dexmedetomidine dosage, making it unreliability in clinical application.Another meta analysis by Zhou et al. [26] showed that the ED90 of intravenous DEX for preventing EA in pediatric patients undergoing dental surgery with sevoflurane anesthesia was 0.74 μg/kg/h.However, their administration route was intravenous.Our network meta-analysis confirmed the anti-ED/ EA efficacy of dexmedetomidine compared to saline, moreover, we concluded that 2 μg/kg was the optimal dosage via aspects of the incidence, severity, and score of ED/ EA.
We revealed intranasal dexmedetomidine reduced pain in PACU, and 2 μg/kg was the optimal dosage.Fu et al. [27] and Tang et al. [28] showed that intravenous dexmedetomidine reduced postoperative pain in children, which was consistent with ours.
There are some limitations in our study.The number of included studies were small and we did not included non-randomized studies not only for they had lots of confounding factors, but there was no non-randomised study(observational or cohort studies) reporting intranasal dexmedetomidine preventing pediatric patients' ED/ EA as well.We did not compare the anti-ED/EA effects of different pathways of dexmedetomidine, such as intravenous, oral route.These are needed future studies.

Fig 2 .
Fig 2. Network plot diagram for the effect of different intranasal dexmedetomidine dosage on outcomes.(A) the incidence of emergence delirium or emergence agitation; (B) the incidence of severe emergence delirium or emergence agitation; (C) Score of Pediatric Anesthesia Emergence Delirium Scale; (D) PACU pain VAS score.The thickness of edges and numbers located on the line represent the number of trials for each direct comparison.https://doi.org/10.1371/journal.pone.0304796.g002

Fig 4 .
Fig 4. The probability of ranking plot for the effect of different intranasal dexmedetomidine dosage on outcomes.(A) the incidence of emergence delirium or emergence agitation; (B) the incidence of severe emergence delirium or emergence agitation; (C) Score of Pediatric Anesthesia Emergence Delirium Scale; (D) PACU pain VAS score.https://doi.org/10.1371/journal.pone.0304796.g004